Opinion: Why paediatric rheumatologists need to understand inborn errors of immunity

Paediatric rheumatologists are referred a wide variety of patients affected by diseases characterised by chronic or recurrent inflammation of the musculoskeletal system and connective tissues. The 'classic' rheumatological diseases include rheumatic fever, juvenile idiopathic arthritis (JIA), the spondyloarthropathies, systemic lupus erythematosus (SLE), juvenile dermatomyositis (JDM), scleroderma, and the vasculitis syndromes. However, a significant number of children present with unexplained fevers, rashes, and various musculoskeletal complaints which do not fit any defined pattern, thus 'making the matter of accurate differential diagnosis extremely important' (Shaller, 2005).Continued paediatric rheumatology education is of utmost importance, primarily for the benefit of patients under their care (McColl et al, 2024;Turnier Sogkas Etzioni, 2003). A seminal report confirmed that autoimmune and inflammatory manifestations frequently complicated PIDs in a large cohort of patients from the French national registry, including autoimmune cytopaenias (31%), gastrointestinal (24%), skin (14%), and rheumatic disorders (13%) (Fischer et al, 2017) In addition to the well-reviewed associations between conventional PIDs (i.e., due to defects in complement, phagocytes, B and T lymphocytes, where affected patients manifest unusual susceptibility to various infectious agents) and rheumatic diseases (Torgerson, 2012), a novel group of disorders of immune dysregulation (or primary immune regulatory disorders, PIRD) became evident, characterized predominantly by autoimmunity, inflammation, or other immune-mediated pathology (Noratangelo et al, 2004;Bonilla et al, 2015;Notarangelo et al, 2020). This led the way to broadening the spectrum of inborn immune system 'failures' associated with rheumatic diseases (Dimitriades Allenspach Mikuska et al, 1983).Resulting deficient classical complement pathway activity was postulated to underpin a failure to clear apoptotic cells leading to exaggerated inflammatory responses. This formed the basis of the 'waste disposal' hypothesis to explain the pathogenesis of SLE (Schifferli et al, 1983;Walport, 2001).In parallel, an entirely novel group of diseases related to periodic fever syndromes initially described in 1950s (Reiman, 1948;Reiman, 1957) was added to the canon, heralded by the finding of MEFV gene mutations as a cause of familial Mediterranean fever (FMF) (The International and French FMF Consortia, 1997; reviewed by Samuels et al, 1998) and of TNFR1 gene mutations defining a family of dominantly inherited autoinflammatory syndromes (McDermot et al, 1999).The everexpanding spectrum of the monogenic autoinflammatory diseases refers to the inborn disorders of the innate immune system, with presentations characterized by episodes of systemic inflammation that are mediated largely by myeloid cells and by lack of autoantibodies and/or autoreactive T lymphocytes, thus distinguishing them from autoimmune diseases (Stoffels Maoghaddas Meertens et al, 2024). Fascinatingly, C1q deficiency is currently understood and classified as an interferonopathy, one of the subcategories of autoinflammatory diseases (Traille et al, 2024).The term 'primary immunologic deficiency (PID)', as per the first report by the World Health Organisation (WHO) Committee on classification of PIDs referred to a group of diseases caused by a failure of either B lymphocyte/humoral immunity and/or of thymus-dependent T lymphocyte immunity, where affected individuals presented with markedly increased susceptibility to various infectious agents manifesting usually (but not exclusively) in early childhood (Fudenberg et al, 1970).Although primary complement and phagocytic cell defects were not initially included, over the next 5 decades the term PID expanded to comprise disorders resulting from mutations in an ever-increasing number of genes involved in immune host defence (both of innate and adaptive immunity) and/or immunoregulation (central/thymic and peripheral tolerance) as evidenced by numerous WHO and later International Union of Immunological Societies (IUIS) Committees updates. However, as stated in the 2017 update "this terminology does limit the conceptualization of disorders to those in which susceptibility to infection is the main manifestation. The improving recognition of immune dysregulation diseases, including the growing field of autoinflammatory disorders and interferonopathies, has mandated that a more encompassing terminology be used", i.e. IEI (Picard et al, 2018).Changes to accepted nomenclature are continuously being debated (Al-Herz Akalu Seidel, 2024;Turvey et al., 2024;Henrickson, 2025) confirming the astute prediction published at the dawn of PIDs coming into existence (Geha, 2005) by one of the pioneers in the field: "Like all hypothetical schemes, based on incomplete knowledge and imperfect interpretation, it must be considered tentative and useful mainly in establishing hypotheses to be demolished by future investigation" (Janeway, 1968).The latest update in the IUIS Committee classification lists 508 different genes known to cause IEIs that can present clinically with various manifestations, from increased susceptibility to infections, autoimmunity, autoinflammation, allergy, bone marrow failure, and/or malignancy (Poli et al, 2025). Importantly for understanding the underlying pathophysiology leading to the phenotypic (clinical) manifestations of these disorders, immunodeficiency (e.g. susceptibility to viral infections) and immune dysregulation caused by different mutation(s) of the same gene (e.g., STAT2) often overlap (Duncan Henderson Labrosse Suntharalingam et al, 2006;Abinun, 2024).It is within this maze of presentations and overlapping phenotypes that paediatric rheumatologists of the day must navigate, explore and eventually succeed in assessing and diagnosing the patient correctly (Abinun Tobin Kindle et al, 2025). The fact that almost half of the newly reported genes underlying IEIs in the previous two years refer to either autoinflammatory or immune dysregulation disorders is a strong proof that the field of IEIs is inseparably intertwined with rheumatology (Poli et al, 2025;Tobin Sullivan, 2021;Gallo et al, 2025;Knight Triaille Gallo 2025).They benefit from collaborative working with their colleagues in paediatric immunology and from managed clinical networks through which experience and learning gleaned from the care of small numbers of children with very rare conditions can be shared more widely. In this way, the ongoing dialogue between immunology and rheumatology continues to enrich both specialities and drives improvements in the care of their patients. Many patients under our care benefited from multidisciplinary team (MDT) approach via combined paediatric rheumatology and Formatted: Font: Bold Formatted: Font: Bold Formatted: Font: Bold immunology clinics (initially set up as 'periodic fever clinics', later combined with other specialities), as well as by national (Ramesh et al, 2010;McCann et al, 2014;Duncan CJA et al, 2018;Altman et al, 2020) and international collaboration (Rensing-Ehl et al, 2010;Leiding et al, 2023;Maccari et al, 2024;Hagele et al, 2024;Buso et al, 2024). Our team contributed to identification of several novel IEI disorders with significant 'rheumatological' phenotypes that were part of their clinical presentation (Angulo et al, 2013;Holzinger et al, 2015;Zhou et al, 2016;Cuchet-Lourenco et al, 2018;Wang et al, 2021;Stremenova Spegarova et al, 2024;van der Made et al, 2024). These are rare diseases, often with no more than a single or handful of patients initially observed by astute clinicians; yet in the following years it transpired that some (e.g. deficiency of adenosine deaminase 2, DADA2) are among the most common monogenic immunodysregulatory and/or autoinflammatory diseases (Lee et al, 2023).Modern genetic testing and cytokine profiling, where available, are powerful tools in the management of rheumatological conditions informing 'precision treatments', although not without caveats (particularly the accurate evaluation and interpretation of results) of which practicing paediatric rheumatologists ought to be aware (Schindewolf et al, 2025;Sullivan, 2021;Gallo et al, 2025;Knight Triaille Dinarello, 2010;Levinson & Wallace, 1992). However, as some patients with monogenic immune dysregulation and/or autoinflammatory disorders are resistant even to the very specific and targeted treatments, there is a valid role for haematopoietic stem cell transplantation (HSCT) in their management (Abinun & Slatter, 2021) and prospect for gene therapy and/or editing in the near future are promising (Rigamonti et al, 2025).Formatted: Font: Bold Formatted: Font: Bold, Italic